1. Field of the Invention
The present invention relates to aminoalkyl substituted 9H-pyridino[2,3-b]indole and 9H-pyrimidino[4,5-b]indole derivatives which selectively bind to corticotropin-releasing factor (CRF1) receptors and to mammalian neuropeptide Y (NPY1) receptors. It further relates to pharmaceutical compositions containing such compounds and the use of such compounds in treating physiological disorders induced or facilitated by CRF or those associated with an excess of neuropeptide Y.
2. Description of the Related Art
Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].
Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].
In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989). Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147(1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].
There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist xcex1-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects that are qualitatively similar to the benzodiazepines [C. W Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the xe2x80x9canxiogenicxe2x80x9d effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro l5-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG 7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].
It has been further postulated that CRF has a role in immunological, cardiovascular or heart-related diseases such as hypertension, tachycardia and congestive heart failure, stroke and osteoporosis. CRF has also been implicated in premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus and colonic hypersensitivity associated with psychopathological disturbance and stress.
The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (xcex1-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C .B Nemeroff eds., CRC Press p221 (1990)].
Neuropeptide Y, a peptide first isolated in 1982, is widely distributed in the central and peripheral neurons and is responsible for a multitude of biological effects in the brain and the periphery. Various animal studies have shown that activation of neuropeptide NPY1 receptors is related to vasoconstriction, Wahlestedt et al., Regul. Peptides, 13: 307-318 (1986), McCauley and Westfall, J. Pharmacol. Exp. Ther. 261 863-868 (1992), and Grundemar et al., Br. J. Pharmacol. 105: 45-50 (1992); and to stimulation of consummatory behavior, Flood and Morley, Peptides, 10: 963-966 (1989), Leibowitz and Alexander, Peptides, 12: 1251-1260 (1991), and Stanley et al., Peptides, 13: 581-587 (1992). Grundemar and Hakanson, TiPS, 15: 153-159 (1994), state that, in animals, neuropeptide Y is a powerful stimuli of food intake, and an inducer of vasoconstriction leading to hypertension. They further point out that low levels of neuropeptide Y is associated with loss of appetite. These reports clearly indicate that compounds that inhibit the activity of this protein will reduce hypertension and appetite in animals.
This invention provides novel compounds of Formula I which interact with CRF1 receptors and NPY1 receptors. It further relates to the use of such compounds, pharmaceutical compositions comprising these compounds, and methods useful for the treatment of psychiatric and affective disorders and neurological diseases, including major depression, headaches, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy, as well as treatment of immunological, cardiovascular or heart-related diseases, hypertension, feeding disorders, diabetes, dislipidemia, colonic hypersensitivity associated with psychopathological disturbance, and stress. It further relates to the use of such compounds in treating physiological disorders induced or facilitated by CRF or those associated with an excess of neuropeptide Y. In particular, this invention provides aminoalkyl substituted 9H-pyridino[2,3-b]indole and 9H-pyrimidino[4,5-b]indole derivatives of Formula I which selectively bind to corticotropin-releasing factor (CRF1) receptors and/or to mammalian neuropeptide Y (NPY1) receptors.
Accordingly, a broad embodiment of the invention is directed to a compound of Formula I: 
wherein
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, carboxamido, N-lower alkyl carboxamido, N,N-lower dialkyl carboxamido, C1-C6 alkyl, C1-C6 alkoxy, with the proviso that at least one of the positions ortho or para to the point of attachment of Ar to the tricyclic ring system is substituted;
R1 is hydrogen, halogen, trifluoromethyl, C1-C6 alkyl, or (C1-C6 alkyl)-G1xe2x80x94R2 where G1 is oxygen or sulfur and R1 is hydrogen or C1-C6 alkyl;
W is N or Cxe2x80x94R3 where R3 is hydrogen or C1-C6 alkyl; and
X is 
xe2x80x83wherein
V1 and V2 are CH2, CO, CS, SO2 or CH(C1-C6 alkyl), with the proviso that both V1 and V2 cannot both be CO, CS or SO2;
Y1 and Y2 independently represent a bond or C1-C6 alkylene;
A1 is NR4R5 wherein R4 and R5 are independently hydrogen, a lower alkyl group which optionally forms a heterocycloalkyl group with Y1;
C1-C6 arylalkyl or C1-C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl,1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring;
lower alkanoyl, lower alkylsulfonyl, with the proviso that R4 and R5 cannot both be alkanoyl or alkylsulfonyl; or
NR4R5 taken together form a C3-C6 heterocycloalkyl or a group of the formula: 
xe2x80x83wherein e and f are independently 1, 2 or 3 and the sum of e and f is at least 3; and
G2 is
xe2x80x83NR6 wherein R6 is hydrogen or C1-C6 alkyl, or CH(C0-C6 alkylene)-G3xe2x80x94R7 wherein G3 is CONH, CONH(C1-C6 alkyl), NH, NH(C1-C6 alkyl) and R7 is hydrogen or C1-C6 alkyl; or
xe2x80x83CONH2, CO[N(C1-C6 alkyl)R8] wherein R8 is hydrogen or C1-C6 alkyl;
xe2x80x83C1-C6 arylalkyl or C1-C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring;
A is hydrogen, C1-C6 alkyl, (C1-C6 alkylene)-G4xe2x80x94R9 wherein G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or C1-C6 alkyl; 
xe2x80x83wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- or disubstituted with halogen, trifluoromethyl, amino, C1-C6 alkyl, C1-C6 alkoxy, with the proviso that tetrazolyl can have at most one substituent;
Z1 is C1-C6 alkyl; and
V2, Y2 and A2 are as defined above; 
xe2x80x83where
Z2 is carbon or nitrogen;
where
xe2x80x83when Z2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R10 is carboxamido, or (C0-C6 alkylene)-G5xe2x80x94R11 wherein G5 is NH, NH(C1-C6 alkyl) and R11 is hydrogen, C1-C6 alkyl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring;
xe2x80x83when Z2 is carbon, n is 1 or 2 and p is 1 or 2, R10 is amino; or
xe2x80x83when Z2 is nitrogen, n is 1 or 2 and p is 1 or 2, R10 is hydrogen; or
(iv) a nitrogen heterocycle of the formula: 
wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (C1-C6 alkylene)-G6xe2x80x94R12 wherein G6 is NH, NH(C1-C6 alkyl) and R12 is hydrogen, C1-C6 alkyl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring.
The compounds of Formula I are antagonists at the CRF1 receptor and are useful in the diagnosis and treatment of stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety.
They are useful in methods for the treatment of psychiatric and affective disorders and neurological diseases, including major depression, headaches, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy, as well as treatment of immunological, cardiovascular or heart-related diseases, hypertension, feeding disorders, diabetes, dislipidemia, colonic hypersensitivity associated with psychopathological disturbance, and stress. Such methods involve administration to a mammal of an effective amount of a compound of the invention.
The compounds of Formula I are also neuropeptide Y1 receptor antagonists, and, therefore, are also of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of neuropeptide Y. The compounds of Formula I have different chemical structures which affect their selectivity towards either the CRF1 or the NPY1 receptors.
The novel compounds encompassed by the instant invention can be described by general Formula I: 
wherein
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, carboxamidb, N-lower alkyl carboxamido, N,N-lower dialkyl carboxamido, C1-C6 alkyl, C1-C6 alkoxy, with the proviso that at least one of the positions ortho or para to the point of attachment of Ar to the tricyclic ring system is substituted;
R1 is hydrogen, halogen, trifluoromethyl, C1-C6 alkyl, or (C1-C6 alkyl)-G1xe2x80x94R2 where G1 is oxygen or sulfur and R2 is hydrogen or C1-C6 alkyl;
W is N or Cxe2x80x94R3 where R3 is hydrogen or C1-C6 alkyl; and
X is 
xe2x80x83wherein
V1 and V2 are CH2, CO, CS, SO2 or CH(C1-C6 alkyl), with the proviso that both V1 and V2 cannot both be CO, CS or SO2;
Y1 and Y2 independently represent a bond or C1-C6 alkylene;
A1 is NR4R5 wherein R4 and R5 are independently hydrogen, a lower alkyl group which optionally forms a heterocycloalkyl group with Y1;
C1-C6 arylalkyl or C1-C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl,1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring;
lower alkanoyl, lower alkylsulfonyl, with the proviso that R4 and R5 cannot both be alkanoyl or alkylsulfonyl; or
NR4R5 taken together form a C3-C6 heterocycloalkyl or a group of the formula: 
xe2x80x83wherein e and f are independently 1, 2 or 3 and the sum of e and f is at least 3; and
G2 is
xe2x80x83NR6 wherein R6 is hydrogen or C1-C6 alkyl, or CH(C0-C6 alkylene)-G3xe2x80x94R7 wherein G3 is CONH, CONH(C1-C6 alkyl), NH, NH(C1-C6 alkyl) and R7 is hydrogen or C1-C6 alkyl; or
xe2x80x83CONH2, CO[N(C1-C6 alkyl)R8] wherein R8 is hydrogen or C1-C6 alkyl;
xe2x80x83C1-C6 arylalkyl or C1-C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring;
A2 is hydrogen, C1-C6 alkyl, (C1-C6 alkylene)-G4xe2x80x94R9 wherein G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or C1-C6 alkyl; 
xe2x80x83wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- or disubstituted with halogen, trifluoromethyl, amino, C1-C6 alkyl, C1-C6 alkoxy, with the proviso that tetrazolyl can have at most one substituent;
Z1 is C1-C6 alkyl; and
V2, Y2 and A2 are as defined above; 
xe2x80x83where
Z2 is carbon or nitrogen;
where
xe2x80x83when Z2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R10 is carboxamido, or (C0-C6 alkylene)-G5xe2x80x94R11 wherein G5 is NH, NH(C1-C6 alkyl) and R11 is hydrogen, C1-C6 alkyl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring;
xe2x80x83when Z2 is carbon, n is 1 or 2 and p is 1 or 2, R10 is amino; or
xe2x80x83when Z2 is nitrogen, n is 1 or 2 and p is 1 or 2, R10 is hydrogen; or
(iv) a nitrogen heterocycle of the formula: 
wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (C1-C6 alkylene)-G6xe2x80x94R12 wherein G6 is NH, NH(C1-C6 alkyl) and R12 is hydrogen, C1-C6 alkyl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring.
Preferred compounds of Formula I include those of Formula IA: 
wherein each Ra is C1-C6 alkyl;
Rb is hydrogen or methyl;
R1 is C1-C6 alkyl;
Rs is C1-C6 alkyl, (C3-C5)cycloalkyl(C1-C3)alkyl, (C1-C3)alkoxy(C1-C3)alkyl, or (C3-C5)cycloalkyl;
t is 1, 2 or 3; and
Rx is hydrogen, C1-C6 alkyl, phenyl(C1-C6)alkyl where phenyl is optionally mono- or disubstituted independently with C1-C6 alkyl, C1-C6 alkoxy, halogen, or hydroxy; and
Ry is hydrogen, C1-C6 alkyl, (C3-C6)cycloalkyl; or
NRxRy represents pyrrolidinyl, N-(C1-C6)alkylpyrrolidin-2-yl, piperidinyl, morpholinyl, or N-(C1-C6)alkylpiperazinyl.
Preferred compounds of Formula IA include those where Rs is C1-C6 alkyl or cyclopropylmethyl. Other preferred compounds of Formula IA include those where Rs is cyclopropyl(C1-C3)alkyl. Still other preferred compounds of Formula IA include those where Rx and Ry independently represent hydrogen or C1-C2 alkyl. More preferred compounds of IA include those where Rs is cyclopropyl(C1-C3)alkyl, Rx and Ry independently represent hydrogen or C1-C2 alkyl; and each Ra is methyl. Particularly preferred compounds of IA are those W is nitrogen.
Other preferred compounds of Formula I include those of Formula IB: 
wherein
each Ra is C1-C6 alkyl;
R1 is C1-C6 alkyl;
Rs is C1-C6 alkyl, cyclopropyl(C1-C3)alkyl or (C1-C3)alkoxy(C1-C3)alkyl;
t is 1 or 2;
Rx is hydrogen, C1-C6 alkyl, phenyl(C1-C6)alkyl where phenyl is optionally mono- or disubstituted independently with C1-C6 alkyl, C1-C6 alkoxy, halogen, or hydroxy; and
Ry is hydrogen, C1-C6 alkyl, (C3-C6)cycloalkyl; or
NRxRy represents pyrrolidinyl, N-(C1-C6)alkylpyrrolidin-2-yl, piperidinyl, morpholinyl, or N-(C1-C6)alkylpiperazinyl.
Preferred compounds of Formula IB include those where Rs is C1-C6 alkyl or cyclopropylmethyl. Other preferred compounds of Formula IB include those where Rs is cyclopropyl(C1-C3)alkyl. Yet other preferred compounds of Formula IB include those where t is 1 and Rx and Ry independently represent hydrogen or C1-C2 alkyl. More preferred compounds of Formula IB include those where Rs is cyclopropyl(C1-C3)alkyl, t is 1 and Rx and Ry independently represent hydrogen or C1-C2 alkyl. Particularly preferred compounds of IB are those where each Ra is methyl, Rs is cyclopropyl(C1-C3)alkyl, t is 1 and Rx and Ry independently represent hydrogen or C1-C2 alkyl. Highly preferred compounds of Formula IB are those where W is nitrogen.
Other preferred compounds of Formula I include those of Formula IC: 
wherein
each Ra is C1-C6 alkyl;
R1 is C1-C6 alkyl;
t is 1 or 2;
Rx and Ry are different and represent hydrogen; (C3-C7)cycloalkylamino (C1-C3)alkyl, carboxamido, (C3-C7)cycloalkylamino, C2-C6 alkanoyl optionally substituted in the xcfx89-position with C1-C6 alkyl or phenyl optionally mono- or disubstituted independently with C1-C6 alkyl, C1-C6 alkoxy, halogen, or hydroxy, provided that at least one of Rx and Ry is hydrogen.
Preferred compounds of Formula IC include those wherein R1 is C1-C2 alkyl and W is nitrogen. Other preferred compounds of IC are those where each Ra is methyl and W is nitrogen.
Other preferred compounds of the invention have Formula II 
wherein
each Ra independently represents C1-C6 alkyl;
R1 is hydrogen, halogen, trifluoromethyl, C1-C6 alkyl, or (C1-C6 alkyl)-G1xe2x80x94R2 where G1 is oxygen or sulfur and R2 is hydrogen or C1-C6 alkyl;
X is 
wherein
V1 and V2 are CH2, CO, CS, SO2 or CH(C1-C6 alkyl), with the proviso that both V1 and V2 cannot both be CO, CS or SO2;
Y1 and Y2 independently represent a bond or C1-C6 alkylene;
A1 is NR4R5 wherein R4 and R5 are independently hydrogen, a lower alkyl group which optionally forms a heterocycloalkyl group with Y1;
C1-C6 arylalkyl or C1-C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, l-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl,1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring;
lower alkanoyl, lower alkylsulfonyl, with the proviso that R4 and R5 cannot both be alkanoyl or alkylsulfonyl; or
NR4R5 taken together form a C3-C6 heterocycloalkyl or a group of the formula: 
xe2x80x83wherein e and f are independently 1, 2 or 3 and the sum of e and f is at least 3; and
G2 is
xe2x80x83NR6 wherein R6 is hydrogen or C1-C6 alkyl, or CH(C0-C6 alkylene)-G3xe2x80x94R7 wherein G3 is CONH, CONH(C1-C6 alkyl), NH, NH(C1-C6 alkyl) and R7 is hydrogen or C1-C6 alkyl; or
xe2x80x83CONH2, CO[N(C1-C6 alkyl)R8] wherein R8 is hydrogen or C1-C6 alkyl;
xe2x80x83C1-C6 arylalkyl or C1-C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring;
A2 is hydrogen, C1-C6 alkyl, (C1-C6 alkylene)-G4xe2x80x94R9 wherein G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or C1-C6 alkyl; 
xe2x80x83wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- or disubstituted with halogen, trifluoromethyl, amino, C1-C6 alkyl, C1-C6 alkoxy, with the proviso that tetrazolyl can have at most one substituent;
Z1 is C1-C6 alkyl; and
V2, Y2 and A2 are as defined above; 
xe2x80x83where
Z2 is carbon or nitrogen;
where
xe2x80x83when Z2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R10 is carboxamido, or (C0-C6 alkylene)-G5xe2x80x94R11 wherein G5 is NH, NH(C1-C6 alkyl) and R11 is hydrogen, C1-C6 alkyl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring;
xe2x80x83when Z2 is carbon, n is 1 or 2 and p is 1 or 2, R10 is amino; or
xe2x80x83when Z2 is nitrogen, n is 1 or 2 and p is 1 or 2, R10 is hydrogen; or
(iv) a nitrogen heterocycle of the formula: 
wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (C1-C6 alkylene)-G6xe2x80x94R12 wherein G6 is NH, NH(C1-C6 alkyl) and R12 is hydrogen, C1-C1 alkyl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring.
Preferred compounds of Formula II are those where V1 and V2 represent methylene; Y1 is a bond; A1 represents pyrrolidinyl, morpholinyl; piperazinyl, mono- or di-C1-C6 alkyl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring; Y2 represents a bond or methylene; and A2 represents C1-C6 alkyl or C1-C6 alkoxymethyl.
Other preferred compounds of the invention have Formula III 
wherein
each Ra independently represents C1-C6 alkyl;
R1 is hydrogen, halogen, trifluoromethyl, C1-C6 alkyl, or (C1-C6 alkyl)-G1xe2x80x94R2 where G1 is oxygen or sulfur and R2 is hydrogen or C1-C6 alkyl; and
X is 
V1 and V2 are CH2, CO, CS, SO2 or CH(C1-C6 alkyl), with the proviso that both V1 and V2 cannot both be CO, CS or SO2;
Y1 and Y2 independently represent a bond or C1-C6 alkylene;
A1 is NR4R5 wherein R4 and R5 are independently hydrogen, a lower alkyl group which optionally forms a heterocycloalkyl group with Y1;
C1-C6 arylalkyl or C1-C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl,1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring;
lower alkanoyl, lower alkylsulfonyl, with the proviso that R4 and R5 cannot both be alkanoyl or alkylsulfonyl; or
NR4R5 taken together form a C3-C6 heterocycloalkyl or a group of the formula: 
xe2x80x83wherein e and f are independently 1, 2 or 3 and the sum of e and f is at least 3; and
G2 is
xe2x80x83NR6 wherein R6 is hydrogen or C1-C6 alkyl, or CH(C0-C6 alkylene)-G3xe2x80x94R7 wherein G3 is CONH, CONH(C1-C6 alkyl), NH, NH(C1-C6 alkyl) and R7 is hydrogen or C1-C6 alkyl; or
xe2x80x83CONH2, CO[(N(C1-C6 alkyl)R8] wherein R8 is hydrogen or C1-C6 alkyl;
xe2x80x83C1-C6 arylalkyl or C1-C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring;
A2 is hydrogen, C1-C6 alkyl, (C1-C6 alkylene)-G4xe2x80x94R9 wherein G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or C1-C6 alkyl; 
xe2x80x83wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- or disubstituted with halogen, trifluoromethyl, amino, C1-C6 alkyl, C1-C6 alkoxy, with the proviso that tetrazolyl can have at most one substituent;
Z1 is C1-C6 alkyl; and
V2, Y2 and A2 are as defined above; 
xe2x80x83where
Z2 is carbon or nitrogen;
where
xe2x80x83when Z2 is CH, n is 0, 1, 2 or 3-and p is 1, 2, or 3, R10 is carboxamido, or (C0-C6 alkylene)-G5xe2x80x94R11 wherein G5 is NH, NH(C1-C6 alkyl) and R11 is hydrogen, C1-C6 alkyl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring;
xe2x80x83when Z2 is carbon, n is 1 or 2 and p is 1 or 2, R10 is amino; or
xe2x80x83when Z2 is nitrogen, n is 1 or 2 and p is 1 or 2, R10 is hydrogen; or
(iv) a nitrogen heterocycle of the formula: 
wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (C1-C6 alkylene)-G6xe2x80x94R12 wherein G6 is NH, NH(C1-C6 alkyl) and R12 is hydrogen, C1-C6 alkyl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring.
Preferred compounds of Formula III are those where V1 and V2 represent methylene; Y1 is a bond; A1 represents pyrrolidinyl, morpholinyl; piperazinyl, mono- or di-C1-C6 alkyl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring; Y2 represents a bond or methylene; and A2 represents C1-C6 alkyl or C1-C6 alkoxymethyl.
Preferred compounds of the invention include:
4-(N-(2-Nxe2x80x2,Nxe2x80x2-Dimethylaminoethyl)-N-ethyl)amino-2-methyl-9-(4-bromo-2,6-dimethylphenyl)-9H-pyrimidino[4,5-b]indole
4-(N-(2-Nxe2x80x2,Nxe2x80x2-Dimethylaminoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Nxe2x80x2,Nxe2x80x2-Dimethylaminoethyl)-N-2-methoxyethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Nxe2x80x2,Nxe2x80x2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Nxe2x80x2-Ethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Nxe2x80x2-Ethyl-Nxe2x80x2-methylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Nxe2x80x2,Nxe2x80x2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(4-methoxy-2-methylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Nxe2x80x2,Nxe2x80x2-Diethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Nxe2x80x2-Methylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Piperidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Pyrrolidinoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Piperidinoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Morpholinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Nxe2x80x2-Ethyl-Nxe2x80x2-methylaminoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Nxe2x80x2,Nxe2x80x2-Dimethylaminoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole
4-(N-(2-(1-Imidazolyl)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Pyrrolidinoethyl)-N-1-oxopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Pyrrolidinoethyl)-N-cyclopropyloxomethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-2-(Nxe2x80x2-Methylpiperazinyl)ethyl-N-cyclopropylmethyl)-amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Pyridylmethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-Piperazinyl-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Aminoethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Aminoethyl)-N-ethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-(4-Triazolyl)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4-dimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(3-Pyrrolidinoproyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-(2-Phenethylamino)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole
4-(N-(2-Pyrrolidinoethyl)-N-2-methoxyethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Pyrrolidinoethyl)-N-ethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Pyrrolidinoethyl)-N-butyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Pyrrolidinoethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Carboxamidoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Pyrrolidinoethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(4-bromo-2,6-dimethylphenyl)-9H-pyrimidino[4,5-b]indole
4-(N-(2-Nxe2x80x2,Nxe2x80x2-Dimethylaminoethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Nxe2x80x2-Ethyl-Nxe2x80x2-methylaminoethyl)-N-2-methylpropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Nxe2x80x2,Nxe2x80x2-Dimethylaminooethyl)-N-propyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole
4-(N-(2-Nxe2x80x2,Nxe2x80x2-Dimethylaminooethyl)-N-butyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole
4-(N-(2-Nxe2x80x2,Nxe2x80x2-Dimethylaminooethyl)-N-cyclopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole
4-(N-(2-(1-Methyl-2-pyrrolidino)ethyl)-N-cyclopropylmethyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyridino[2,3-b]indole
4-(N-(2-Nxe2x80x2,Nxe2x80x2-Dimethylaminoethyl)-N-cyclobutyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole
4-(N-(2-Nxe2x80x2,Nxe2x80x2-Dimethylaminoethyl)-N-isopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole
4-(N-(2-Pyrrolidinoethyl)-N-isopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole
4-(N-(2-Nxe2x80x2,Nxe2x80x2-Dimethylaminoethyl)-N-isopropyl)amino-2-methyl-9-(2,4,6-trimethylphenyl)-9H-pyrimidino[4,5-b]indole
In certain situations, the compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table I and their pharmaceutically acceptable acid addition salts. In addition, if the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOCxe2x80x94(CH2)n-COOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.
By xe2x80x9calkylxe2x80x9d, xe2x80x9clower alkylxe2x80x9d, or C1-C6 alkyl in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms optionally forming a 3 to 6 atoms carbocycle, such as, for example, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, 2-pentyl, isopentyl, neopentyl, cyclopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, cyclohexyl.
By C0-C6 alkylene is meant a direct bond or a C1-C6 alkylene group, optionally forming a 3 to 6 atoms carbocycle, such as methylene, ethylidene, propylidene, butylidene, pentylidene, cyclopentylidene, hexylidene, cyclohexylidene.
By xe2x80x9calkoxyxe2x80x9d, xe2x80x9clower alkoxyxe2x80x9d, or C1-C6 alkoxy in the present invention is meant straight or branched chain alkoxy groups having 1-6 carbon atoms optionally forming a 3 to 6 atoms carbocycle, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, cyclopropylmethoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, cyclopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, cyclohexoxy.
By xe2x80x9calkanoylxe2x80x9d, xe2x80x9clower alkanoylxe2x80x9d, or C1-C6 alkanoyl as used herein is meant straight or branched chain alkanoyl groups having 1-6 carbon atoms optionally forming a 3 to 6 atom carbocycle, such as, for example, acetyl, propionyl, isopropionyl, cyclopropionyl, butanoyl, pentanoyl, cyclopentanoyl, hexanoyl, cyclhexanoyl. The xe2x80x9cxcfx89-positionxe2x80x9d of the alkanoyl groups herein is the terminal carbon atom.
CONH represents an amide functional group, i.e., 
The term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocycloalkylxe2x80x9d means a monocyclic or bicyclic hydrocarbon group which in which one or more of the ring carbon atoms has been replaced with a heteroatom, e.g., oxygen, sulfur or nitrogen. Such groups preferably have 4 to 10 carbon atoms and 1 to 4 heteroatoms.
By the term xe2x80x9chalogenxe2x80x9d in the present invention is meant fluorine, bromine, chlorine, and iodine.
Representative aminoalkyl substituted 9H-pyridino[2,3-b]indole and 9H-pyrimidino[4,5-b]indole derivatives of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Examples 1-18 and their pharmaceutically acceptable addition salts.
The interaction of aminoalkyl substituted 9H-pyridino[2,3-b]indole and 9H-pyrimidino[4,5-b]indole derivatives of the invention with CRF1 and NPY1 receptors is shown in the examples. This interaction results in the pharmacological activities of these compounds as illustrated in relevant animal models.
The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachid oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachid oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general Formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
Dosage levels of the order of from about 0.1 xc3x9cmg to about 140 xc3x9cmg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5xc3x9cmg to about 7xc3x9cg per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 xc3x9cmg to about 500 xc3x9cmg of an active ingredient.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
An illustration of the preparation of compounds of the present invention is given in Scheme I, Scheme II and Scheme III. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention. 
wherein Ar, R1 and R1 are as defined above for Formula I; and R14, R15 and R16 are encompassed by the definition of X as defined in Formula I. 
wherein Ar, R1 and R2 are as defined above for Formula I; and R15 and R16 are encompassed by the definition of X as defined in Formula I. 
wherein Ar and R1 are as defined as above for Formula I; and R15, R16 and R17 are encompassed by the definition of X as defined in Formula I.
The disclosures of all articles and references mentioned in this application, including patents, are incorporated herein by reference.